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Saeko Takada

Research Assistant Professor

Biochemistry, Molecular Biology, and Biophysics

Expertise:

DNA damage responses, Eukaryotic cells and development

Research Description

Living organisms employ a variety of DNA damage responses to prevent permanent genomic damage. Divergent health problems, including cancer, neurodegenerative disorders, immune deficiencies, and infertility could arise from a failure of DNA damage response. DNA damage responses are indispensable in various tissues at different life stages, including during development. In evolutionally conserved DNA damage singling pathways, DNA lesions such as double-strand breaks recruit sensors and mediators that initiate DNA damage signaling, including MRN (Mre11/Rad50/Nbs1) complex and protein kinases such as ATM (Ataxia-Telangiectasia Mutated) and ATR (ATM and Rad3-related) to the damage sites. These kinases phosphorylate a second subset of protein kinases called effector kinases that include Chk1 and Chk2.The activated effector kinase targets and phosphorylates a wide range of downstream proteins that are directly involved in different cellular processes such as cell cycle control, DNA repair, transcription, regulation of cytoskeleton, and mitosis. My laboratory studies how the effector kinase targets divergent substrates in the cell and how it impacts specific cellular processes.

We currently focus on studying mechanisms of embryonic DNA damage responses. We use a Drosophila model system for our research, since this system allows us to utilize genetics, high quality in vivo imaging, and biochemical approaches to study DNA damage responses in the context of development. In early Drosophila embryos, DNA damage disrupts mitosis. It also inhibits normal nuclear positioning, cell-cycle remodeling, activation of zygotic transcription, and cellularization. A conserved tumor suppressor Chk2 is essential for these embryonic DNA damage responses. In somatic cells, Chk2 is known to affect cellular functions including cell cycle checkpoints, apoptosis, DNA repair, RNA processing, and transcription, after DNA damage. Taking full advantage of the Drosophila model system, we have uncovered remarkably dynamic behavior of Chk2 throughout the cell cycle in early embryos. Chk2 mobility and dynamic behavior appear to play important roles to efficiently target the kinase to its substrates throughout the cell. We investigate relationship between Chk2 localization/dynamics and its functions, by combining genetics, confocal imaging, and in vivo analyses of mutant protein functions. In addition, we aim to identify Chk2 binding partner(s) and/or target(s) at the cellular structures where Chk2 localizes, using proteomic approaches. We anticipate understanding molecular mechanisms of the embryonic DNA damage responses that link genome integrity to control of mitosis and developmental progression. Our study should provide us with a paradigm and tools to investigate whether similar DNA damage responses operate in mammals.